The pathophysiology of type 2 diabetes involves inadequate insulin secretion from pancreatic [unreadable]-cells in the islet of Langerhans. Islet endocrine cells secrete hormones in response to physiologic stimuli such as glucose, metabolites, other hormones, and neural signals. This coordinated response depends on communication between endocrine, endothelial, and neural cells within the islet. The goal of these studies is to provide a better understanding of the factors that mediate the co-development of islet cells to form a functional endocrine organ. Cre-lox-mediated inactivation of pancreatic vascular endothelial growth factor A (VEGF-A) leads to reduced islet vascularization and impaired insulin secretion. Unexpectedly, reduced VEGF-A also impairs islet innervation. The first aim of this proposal is to examine the development of pancreatic islet innervation and elucidate the mechanism by which VEGF-A directs this process. First, the development of islet vascular and neural structures during the embryonic and postnatal periods will be followed in mice with pancreatic VEGF-A inactivation and in their wild-type counterparts. Next, in vitro cell migration assays will be used to reveal whether islet cell-derived VEGF-A or intra-islet endothelial cells mediate the recruitment of neural cells. These experiments will help determine the co-dependence of islet cells during islet formation. The second aim of this proposal will focus on the role of peri-islet Schwann cells, which undergo reactive gliosis in response to inactivation of pancreatic VEGF-A. Peri-islet Schwann cells will be ablated in mice using cell-specific expression of a toxin receptor, and the effects on islet cell organization, innervation, and function will be assessed. These studies will elucidate the role of peri-islet Schwann cells, whose role in islet function is currently unknown. RELEVANCE One central defect in type 2 diabetes is inadequate insulin secretion from pancreatic [unreadable]-cells, so understanding [unreadable]-cell function and dysfunction is of critical importance. These studies will determine how [unreadable] cells, blood vessels, and nerves in the pancreatic islet signal to each other, both during development and in the adult, and elucidate how these relationships are necessary for proper insulin secretion. A better understanding of islet development and function and could lead to improved therapeutic approaches for diabetes.